A concise synthesis of (+)-batzelladine B from simple pyrrole-based starting materials

Abstract

Alkaloids, secondary metabolites that contain basic nitrogen atoms, are some of the most well-known biologically active natural products in chemistry and medicine1. Although the efficient laboratory syntheses of alkaloids would enable researchers to study and optimize their biological properties,2 the basicity and nucleophilicity of nitrogen, its susceptibility to oxidation, and its ability to alter reaction outcomes in unexpected ways – for example, through stereochemical instability and neighboring group participation – complicates their preparation in the laboratory. Efforts to address these issues have led to the invention of a large number of protecting groups that temper the reactivity of nitrogen3; however, the use of protecting groups typically introduce additional steps and obstacles into the synthetic route. Alternatively, the use of aromatic nitrogen heterocycles as synthetic precursors can attenuate the reactivity of nitrogen and streamline synthetic strategies4. In this manuscript, we use such an approach to achieve a synthesis of the complex anti-HIV alkaloid (+)-batzelladine B in nine steps (longest-linear sequence) from simple pyrrole-based starting materials. The route employs several key transformations that would be challenging or impossible to implement using saturated nitrogen heterocycles and highlights some of the advantages conferred by the use of aromatic starting materials.

Auto‐Tandem Catalysis: Activation of Multiple, Mechanistically Distinct Process by a Single Catalyst

“…Importantly, the researchers were able to monitor the progress of the reaction using F 19 NMR and showed that the reduction of aldehydes 105 only occurred after all of the starting material acetylenes 104 was consumed. Further advancements using this concept allowed for the synthesis of alcohols, 1,3‐amino alcohols, 1,3‐diols, amines and carboxylic acids from terminal alkynes as well as the total synthesis of the natural product (+)‐batzelladine B …”

“…Further advancements using this concept allowed for the synthesis of alcohols, [65] 1,3-amino alcohols, 1,3-diols, amines and carboxylic acids from terminal alkynes [66] as well as the total synthesis of the natural product (+)-batzelladine B. [67] Scheme 25. Application of temporal separation to an ATC process.…”

Cycloaddition reactions of enoldiazo compounds

“…147 It is worth mentioning that simple vinyldiazoacetate (in the absence of β-silyloxy group) only gave moderate yields and enantioselectivities (up to 58% yield and 65% ee). 147 The potential of this strategy was fully illustrated by upscaling to multi-gram quantities 146 and by the syntheses of (−)-anhydroecgonine methyl ester, 146 (−)-ferruginine, 146 isostemofoline, 147 (+)-batzelladine B, 148 and scopolamine. 149 …”

Chemistry: Why synthesize?

“…Every year brings its bounty. In 2015, chemists published a new and elegant route to the anticancer drug paclitaxel (Taxol) 1 , and syntheses of a nodulisporic acid that might act as an insecticide 2 and, in this journal, of an anti-HIV alkaloid 3 . There are also less utilitarian reasons for making molecules.…”